| dc.description.abstract | G6PC2 encodes a glucose-6-phosphatase catalytic subunit that is highly expressed in pancreatic islet beta cells. Genome wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the G6PC2 gene are associated with variations in fasting blood glucose (FBG), a parameter linked with risk for type 2 diabetes (T2D) and cardiovascular-associated mortality (CAM). G6PC2 hydrolyzes glucose-6-phosphate to glucose and inorganic phosphate, creating a futile substrate cycle that opposes the action of glucokinase, determining the sensitivity of glucose-stimulated insulin secretion to glucose and hence regulating FBG levels. G6PC2 is highly expressed in human and mouse beta cells, however, studies have shown trace expression in multiple tissues, raising the possibility that G6PC2 also affects FBG through non-islet cell actions. We show here that in adult mice, beta cell-specific deletion of G6pc2 was sufficient to reduce FBG. Additionally, electronic health record-derived phenotype analyses showed no association between G6PC2 expression and phenotypes clearly unrelated to islet function in humans. To investigate potential physiological roles for G6PC2, we examined the response of wild type (WT) and G6pc2 knockout (KO) mice to changes in nutrition. When challenged with either a ketogenic diet or 24 hour fasting, FBG fell to 70 mg/dl or less in G6pc2 KO but not WT mice, suggesting that G6PC2 may have evolved, in part, to prevent hypoglycemia. In contrast, hyperglycemia associated with high fat feeding was partially blunted in G6pc2 KO mice, suggesting that under these conditions the presence of G6PC2 is detrimental. Finally, we showed SNPs that alter conserved residues in G6PC2 have variable effects on protein expression with several resulting in a marked decrease in expression. These studies suggest that G6PC2 inhibitors would be useful for lowering FBG and thereby lowering the risk of CAM and T2D, but partial inhibition will be important to avoid the risk of hypoglycemia. | |
